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  • 1.
    Ahlström, Tommy
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Hagström, Emil
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Larsson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Biochemial structure and function.
    Rudberg, Claes
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centre for Clinical Research, County of Västmanland.
    Lind, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiovascular epidemiology.
    Hellman, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Correlation between plasma calcium, parathyroid hormone (PTH) and the metabolic syndrome (MetS) in a community-based cohort of men and women2009In: Clinical Endocrinology, ISSN 0300-0664, E-ISSN 1365-2265, Vol. 71, no 5, p. 673-678Article in journal (Refereed)
    Abstract [en]

    CONTEXT: In recent years, an association has been noted between several abnormalities that characterize the metabolic syndrome (MetS) and primary hyperparathyroidism (pHPT). These abnormalities include dyslipidaemia, obesity, insulin resistance and hypertension. The correlations between plasma calcium, parathyroid hormone (PTH) and the variables in the MetS in a normal population are still unclear.

    OBJECTIVE: To describe correlations between plasma calcium and PTH and the various abnormalities present in the MetS in a healthy population.

    DESIGN: We studied 1016 healthy individuals from the Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS) population of 70 years old, by means of plasma analyses of calcium, PTH, creatinine, lipids, insulin and glucose, as well as by standardized blood pressure measurements. Further, body mass index (BMI) and waist circumference were determined.

    RESULTS: The more National Cholesterol Education Program (NCEP) criteria for the MetS that were met, the higher the s-PTH and albumin-corrected s-calcium. Further, positive correlations between plasma calcium and BMI (P = 0.0003), waist circumference (P = 0.0009) and insulin resistance (P = 0.079) were found. PTH and BMI (P < 0.0001), waist circumference (P < 0.0001), systolic blood pressure (P = 0.0034), diastolic blood pressure (P = 0.0008), serum triglycerides (P = 0.0003) and insulin resistance (P = 0.0003) were positively correlated, whereas serum high density lipoproteins (HDL) (P = 0.036) and PTH were negatively correlated.

    CONCLUSIONS: We conclude that PTH correlates with several of the metabolic factors included in the MetS within a normocalcaemic population. In addition, individuals with mild pHPT present significantly more NCEP criteria for MetS. We postulate that increased levels of PTH in pHPT may be associated with the increased cardiovascular morbidity and mortality seen in pHPT.

  • 2. Barbaro, Michela
    et al.
    Oscarson, Mikael
    Almskog, Ingrid
    Hamberg, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Wedell, Anna
    Complete androgen insensitivity without Wolffian duct development: the AR-A form of the androgen receptor is not sufficient for male genital development2007In: Clinical Endocrinology, ISSN 0300-0664, E-ISSN 1365-2265, Vol. 66, no 6, p. 822-826Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: The androgen receptor (AR) is essential for the differentiation of male external and internal genitalia. It is normally present in two forms, a full-length form B and an N-terminal truncated form A with still unknown function. Mutations in the AR gene cause androgen insensitivity syndrome (AIS), which is divided into subgroups according to the degree of undermasculinization. Patients with completely female external genitalia are classified as complete AIS (CAIS). However, a recent study has shown that some CAIS patients have signs of internal male genital differentiation due to missense mutations that show some degree of residual function. OBJECTIVE: We aimed to study the expression of the different forms of the AR in two CAIS patients in relation to the development of male internal genital structures. One patient had a mutation (L7fsX33) that affects only the full-length AR-B form of the AR, whereas the other had a nonsense mutation (Q733X) affecting both isoforms. MEASUREMENTS AND RESULTS: We thoroughly analysed internal genitalia at surgery and by histological examination. No signs of Wolffian duct (WD) development were present in any of the patients. Western blotting of proteins from gonadal and genital skin fibroblasts was performed with AR antibodies directed against different AR epitopes. The N-terminally truncated A form was expressed in normal amounts in the patient with the L7fsX33 mutation while no AR was detected in the other patient. CONCLUSION: The presence of the AR-A form does not seem to be sufficient for WD maintenance and differentiation.

  • 3. Barbaro, Michela
    et al.
    Soardi, Fernanda C.
    Ostberg, Linus J.
    Persson, Bengt
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Computational and Systems Biology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    de Mello, Maricilda Palandi
    Wedell, Anna
    Lajic, Svetlana
    In vitro functional studies of rare CYP21A2 mutations and establishment of an activity gradient for nonclassic mutations improve phenotype predictions in congenital adrenal hyperplasia2015In: Clinical Endocrinology, ISSN 0300-0664, E-ISSN 1365-2265, Vol. 82, no 1, p. 37-44Article in journal (Refereed)
    Abstract [en]

    BackgroundA detailed genotype-phenotype evaluation is presented by studying the enzyme activities of five rare amino acid substitutions (Arg233Gly, Ala265Ser, Arg341Trp, Arg366Cys and Met473Ile) identified in the CYP21A2 gene in patients investigated for Congenital adrenal hyperplasia (CAH). ObjectiveTo investigate whether the mutations identified in the CYP21A2 gene are disease causing and to establish a gradient for the degree of enzyme impairment to improve prediction of patient phenotype. Design and patientsThe CYP21A2 genes of seven patients investigated for CAH were sequenced and five mutations were identified. The mutant proteins were expressed in vitro in COS-1 cells, and the enzyme activities towards the two natural substrates were determined to verify the disease-causing state of the mutations. The in vitro activities of these rare mutations were also compared with the activities of four mutations known to cause nonclassic CAH (Pro30Leu, Val281Leu, Pro453Ser and Pro482Ser) in addition to an in silico structural evaluation of the novel mutants. Main outcome measureTo verify the disease-causing state of novel mutations. ResultsFive CYP21A2 mutations were identified (Arg233Gly, Ala265Ser, Arg341Trp, Arg366Cys and Met473Ile). All mutant proteins exhibited enzyme activities above 5%, and four mutations were classified as nonclassic and one as a normal variant. By comparing the investigated protein changes with four common mutations causing nonclassic CAH, a gradient for the degree of enzyme impairment could be established. Studying rare mutations in CAH increases our knowledge regarding the molecular mechanisms that render a mutation pathogenic. It also improves phenotype predictions and genetic counselling for future generations.

  • 4.
    Bensing, Sophie
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Brandt, Lena
    Tabaroj, Farnoush
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Sjöberg, Olof
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Clinical Immunology and Transfusion Medicine.
    Nilsson, Bo
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Clinical Immunology.
    Ekbom, Anders
    Blomqvist, Paul
    Kämpe, Olle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Increased death risk and altered cancer incidence pattern in patients with isolated or combined autoimmune primary adrenocortical insufficiency2008In: Clinical Endocrinology, ISSN 0300-0664, E-ISSN 1365-2265, Vol. 69, no 5, p. 697-704Article in journal (Refereed)
    Abstract [en]

    OBJECTIVES: Primary adrenocortical insufficiency is mostly caused by an autoimmune destruction of the adrenal cortex. The disease may appear isolated or as a part of an autoimmune polyendocrine syndrome (APS). APS1 is a rare hereditary disorder with a broad spectrum of clinical manifestations. In APS2, primary adrenocortical insufficiency is often combined with autoimmune thyroid disease and/or type 1 diabetes. We analysed mortality and cancer incidence in primary adrenocortical insufficiency patients during 40 years. Data were compared with the general Swedish population. DESIGN AND PATIENTS: A population based cohort study including all patients with autoimmune primary adrenocortical insufficiency (3299) admitted to Swedish hospitals 1964-2004. MEASUREMENTS: Mortality risk was calculated as the standardized mortality ratio (SMR) and cancer incidence as the standardized incidence ratio (SIR). RESULTS: A more than 2-fold increased mortality risk was observed in both women (SMR 2.9, 95% CI 2.7-3.0) and men (SMR 2.5, 95% CI 2.3-2.7). Highest risks were observed in patients diagnosed in childhood. SMR was higher in APS1 patients (SMR 4.6, 95% CI 3.5-6.0) compared with patients with APS2 (SMR 2.1, 95% CI 1.9-2.4). Cancer incidence was increased (SIR 1.3, 95% CI 1.2-1.5). When tumours observed during the first year of follow-up were excluded, only the cancer risk among APS1 patients remained increased. Cause-specific cancer incidence analysis revealed significantly higher incidences of oral cancer, nonmelanoma skin cancer, and male genital system cancer among patients. Breast cancer incidence was lower than in the general population. CONCLUSIONS: Our study shows a reduced life expectancy and altered cancer incidence pattern in patients with autoimmune primary adrenocortical insufficiency.

  • 5. Bjornsdottir, Sigridur
    et al.
    Oksnes, Marianne
    Isaksson, Magnus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Autoimmunity.
    Methlie, Paal
    Nilsen, Roy M.
    Hustad, Steinar
    Kämpe, Olle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Autoimmunity.
    Hulting, Anna-Lena
    Husebye, Eystein S.
    Lovas, Kristian
    Nystrom, Thomas
    Bensing, Sophie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Autoimmunity.
    Circadian hormone profiles and insulin sensitivity in patients with Addison's disease: a comparison of continuous subcutaneous hydrocortisone infusion with conventional glucocorticoid replacement therapy2015In: Clinical Endocrinology, ISSN 0300-0664, E-ISSN 1365-2265, Vol. 83, no 1, p. 28-35Article in journal (Refereed)
    Abstract [en]

    ContextConventional glucocorticoid replacement therapy in patients with Addison's disease (AD) is unphysiological with possible adverse effects on mortality, morbidity and quality of life. The diurnal cortisol profile can likely be restored by continuous subcutaneous hydrocortisone infusion (CSHI). ObjectiveThe aim of this study was to compare circadian hormone rhythms and insulin sensitivity in conventional thrice-daily regimen of glucocorticoid replacement therapy with CSHI treatment in patients with AD. Design and settingAn open, randomized, two-period, 12-week crossover multicentre trial in Norway and Sweden. PatientsTen Norwegian patients were admitted for 24-h sampling of hormone profiles. Fifteen Swedish patients underwent euglycaemic-hyperinsulinaemic clamp. InterventionThrice-daily regimen of oral hydrocortisone (OHC) and CSHI treatment. Main outcome measureWe measured the circadian rhythm of cortisol, adrenocorticotropic hormone (ACTH), growth hormone (GH), insulin-like growth factor-1, (IGF-1), IGF-binding protein-3 (IGFBP-3), glucose, insulin and triglycerides during OHC and CSHI treatment. Euglycaemic-hyperinsulinaemic clamp was used to assess insulin sensitivity. ResultsContinuous subcutaneous hydrocortisone infusion provided a more physiological circadian cortisol curve including a late-night cortisol surge. ACTH levels showed a near normal circadian variation for CSHI. CSHI prevented a continuous decrease in glucose during the night. No difference in insulin sensitivity was observed between the two treatment arms. ConclusionContinuous subcutaneous hydrocortisone infusion replacement re-established a circadian cortisol rhythm and normalized the ACTH levels. Patients with CSHI replacement had a more stable night-time glucose level compared with OHC without compromising insulin sensitivity. Thus, restoring night-time cortisol levels might be advantageous for patients with AD.

  • 6.
    Carlzon, Daniel
    et al.
    Univ Gothenburg, Inst Med, Sahlgrenska Acad CBAR, Ctr Bone & Arthrit Res, Gothenburg, Sweden..
    Svensson, Johan
    Univ Gothenburg, Inst Med, Sahlgrenska Acad CBAR, Ctr Bone & Arthrit Res, Gothenburg, Sweden..
    Petzold, Max
    Univ Gothenburg, Sahlgrenska Acad, Ctr Appl Biostat, Gothenburg, Sweden..
    Karlsson, Magnus K.
    Lund Univ, Skane Univ Hosp, Dept Orthopaed & Clin Sci, Clin & Mol Osteoporosis Res Unit, Malmo, Sweden..
    Ljunggren, Östen
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrinology and mineral metabolism.
    Haghsheno, Mohammad-Ali
    Univ Gothenburg, Inst Clin Sci, Dept Urol, Gothenburg, Sweden..
    Damber, Jan-Erik
    Univ Gothenburg, Inst Clin Sci, Dept Urol, Gothenburg, Sweden..
    Mellström, Dan
    Univ Gothenburg, Inst Med, Sahlgrenska Acad CBAR, Ctr Bone & Arthrit Res, Gothenburg, Sweden..
    Ohlsson, Claes
    Univ Gothenburg, Inst Med, Sahlgrenska Acad CBAR, Ctr Bone & Arthrit Res, Gothenburg, Sweden..
    Insulin-like growth factor I and risk of incident cancer in elderly men - results from MrOS (Osteoporotic Fractures in Men) in Sweden2016In: Clinical Endocrinology, ISSN 0300-0664, E-ISSN 1365-2265, Vol. 84, no 5, p. 764-770Article in journal (Refereed)
    Abstract [en]

    ObjectiveStudies of the association between circulating IGF-I and cancer risk have shown conflicting results. We have previously observed a U-shaped association between IGF-I and cancer mortality. This study test the hypotheses of a U-shaped association between IGF-I and incident cancer. DesignElderly men (2368), randomly recruited from the general community. MethodsIGF-I was measured in a cohort of elderly men. Complete data for incident cancer were obtained from the Swedish Cancer Registry. Statistical analyses included Cox proportional hazards regressions with or without a spline approach. ResultsThree hundred and sixty-nine participants had incident cancer after baseline. Prostate cancer was most frequent (n = 140). There was no association between serum IGF-I and all cancer or prostate cancer incidence. However, there was a nonlinear association between IGF-I and nonprostate cancer incidence (P = <005). Exploratory analyses were performed for low and high serum IGF-I (quintiles 1 and 5) vs intermediate (quintiles 2-4, referent). There was a tendency of increased nonprostate cancer risk in men with high IGF-I (HR = 126, 95% confidence interval (CI): 092-171, P = 015). After excluding participants with follow-up of less than 26 years (half median follow-up time), to control for potential diagnostic delay, the association was statistically significant (HR = 155, CI: 103-235). ConclusionThere was a significant nonlinear association between IGF-I and nonprostate cancer. No association between IGF-I and prostate cancer was observed. Future studies are warranted to further investigate this nonlinear association, including whether IGF-I concentration is a reproducible, and useful, risk marker of nonprostate cancer.

  • 7. Cervato, Sara
    et al.
    Morlin, Luca
    Albergoni, Maria Paola
    Masiero, Stefano
    Greggio, Nella
    Meossi, Cristiano
    Chen, Shu
    Larosa, Maria del Pilar
    Furmaniak, Jadwiga
    Smith, Bernard Rees
    Alimohammadi, Mohammad
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Kämpe, Olle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Valenzise, Mariella
    Betterle, Corrado
    AIRE gene mutations and autoantibodies to interferon omega in patients with chronic hypoparathyroidism without APECED2010In: Clinical Endocrinology, ISSN 0300-0664, E-ISSN 1365-2265, Vol. 73, no 5, p. 630-636Article in journal (Refereed)
    Abstract [en]

    Objective To assess autoimmune regulator (AIRE) gene mutations, class II HLA haplotypes, and organ- or non-organ-specific autoantibodies in patients with chronic hypoparathyroidism (CH) without associated Addison's disease (AD) or chronic candidiasis (CC). Patients and Measurements Twenty-four patients who had CH without AD or CC were included in the study. AIRE gene mutations in all 14 exons were studied using PCR in 24 patients, 105 healthy controls and 15 first-degree relatives of CH patients with AIRE mutations. Human leucocyte antigens (HLA) were determined for all 24 patients and 105 healthy controls. Autoantibodies to a range of antigens including NACHT leucine-rich-repeat protein-5 (NALP5) and interferon omega (IFN omega) were tested in all 24 patients. Results AIRE gene mutations were found in 6 of 24 (25%) patients, all females, and this was significantly higher (P < 0.001) compared with AIRE mutations found in healthy controls (2/105). Three patients (12.5%) had homozygous AIRE mutations characteristic of Autoimmune-Poly-Endocrinopathy-Candidiasis-Ectodermal-Dystrophy and all three were also positive for IFN omega-autoantibodies. Three patients (12.5%) had heterozygous AIRE mutations; two of these were novel mutations. One of the patients with heterozygous AIRE mutations was positive for both NACHT leucine-rich-repeat protein 5 and IFN omega autoantibodies. Heterozygous AIRE mutations were found in 10 of 15 first-degree relatives of CH patients with AIRE mutations, although none was affected by CH. Class II HLA haplotypes were not statistically different in patients with CH compared to healthy controls. Conclusions Analysis of AIRE gene mutations together with serum autoantibody profile should be helpful in the assessment of patients with CH, in particular young women with associated autoimmune diseases.

  • 8.
    Daskalakis, Kosmas
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery. Univ Athens, Laiko Hosp, Dept Propauped Internal Med 1, Endocrine Oncol Unit, Athens, Greece.
    Tsoli, Marina
    Univ Athens, Laiko Hosp, Dept Propauped Internal Med 1, Endocrine Oncol Unit, Athens, Greece.
    Karapanagioti, Angeliki
    Univ Athens, Laiko Hosp, Dept Propauped Internal Med 1, Endocrine Oncol Unit, Athens, Greece.
    Chrysochoou, Maria
    Univ Athens, Laiko Hosp, Dept Propauped Internal Med 1, Endocrine Oncol Unit, Athens, Greece.
    Thomas, Dimitrios
    Univ Athens, Laiko Hosp, Dept Propauped Internal Med 1, Endocrine Oncol Unit, Athens, Greece.
    Sougioultzis, Stavros
    Univ Athens, Laikon Univ Hosp, Dept Pathophysiol, Gastroenterol Div, Athens, Greece.
    Karoumpalis, Loannis
    G Gennimatas Gen Hosp, Dept Gastroenterol, Athens, Greece.
    Kaltsas, Gregory A.
    Univ Athens, Laiko Hosp, Dept Propauped Internal Med 1, Endocrine Oncol Unit, Athens, Greece.
    Alexandraki, Krystallenia, I
    Univ Athens, Laiko Hosp, Dept Propauped Internal Med 1, Endocrine Oncol Unit, Athens, Greece.
    Recurrence and metastatic potential in Type 1 gastric neuroendocrine neoplasms2019In: Clinical Endocrinology, ISSN 0300-0664, E-ISSN 1365-2265, Vol. 91, no 4, p. 534-543Article in journal (Refereed)
    Abstract [en]

    Background The aim of our study was to assess clinico-pathological and biochemical parameters of Type 1 Gastric Neuroendocrine Neoplasms (GNEN1) with respect to tumours propensity for recurrence and metastasis. Methods Hospital charts of GNEN1 patients were reviewed at a single tertiary referral centre. Results We included 114 consecutive patients (74 women; age at baseline 54.5 +/- 12.7 years [mean +/- SD]) with GNEN1. All tumours (n = 114) were well differentiated; Grade 1 (G1) accounted for 56 patients (49%), whereas 46 (40%) were Grade 2 (G2) and 12 (11%) of unknown Grade. Overall follow-up encompassed 45.3 +/- 46 (mean +/- SD) months in 84 patients who were subjected to annual surveillance; 44 (52%) developed recurrence in the stomach during follow-up with 22 experiencing multiple recurrences; three (2.6%) presented with metastases in locoregional lymph nodes (n = 3) and/or the liver (n = 2); No metastasis or death was reported during follow-up. Median recurrence-free survival (RFS) was 31 months (95% CI: 7.6-54.4). Among clinico-pathological and biochemical parameters investigated, endoscopic intervention compared with surgery (P-value = .009) and higher serum-gastrin levels (s-gastrin) at baseline and first-year follow-up were associated with recurrence (P-value = .022 and .003 respectively) and also shorter RFS (log-rank P = .009 for type of intervention and .014 for s-gastrin, respectively). Receiver Operator Curve analysis of s-gastrin levels at first-year follow-up for recurrence demonstrated an area under the curve of 0.702. Conclusion Despite the relatively high prevalence of G2 tumours, endoscopically and/or surgically treated GNEN1 remains an indolent disease with a low metastatic propensity and no disease-specific mortality reported in our series. Many patients though will experience local recurrence, warranting long-term endoscopic surveillance with s-gastrin biomarker being a complementary tool in recurrence prediction.

  • 9. Decker, Ralph
    et al.
    Albertsson-Wikland, Kerstin
    Kristrom, Berit
    Halldin, Maria
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Pediatrics.
    Dahlgren, Jovanna
    Decreased GH dose after the catch-up growth period maintains metabolic outcome in short prepubertal children with and without classic GH deficiency2012In: Clinical Endocrinology, ISSN 0300-0664, E-ISSN 1365-2265, Vol. 77, no 3, p. 407-415Article in journal (Refereed)
    Abstract [en]

    Objective Few studies have evaluated metabolic outcomes following growth hormone (GH) treatment in short prepubertal children during different periods of growth. Previously, we found that individualized GH dosing in the catch-up period reduced the variation in fasting insulin levels by 34% compared with those receiving a standard GH dose. We hypothesized that the GH dose required to maintain beneficial metabolic effects is lower during the prepubertal growth phase after an earlier catch-up growth period.

    Design Short prepubertal children with isolated GH deficiency or idiopathic short stature were randomized to individualized GH treatment (range, 17100 mu g/kg/day) or a standard dose in a preceding 2-year study. After achieving near mid-parental heightSDS, children receiving an individualized dose were randomized to either a 50% reduced individualized dose (RID, n=28) or an unchanged individualized dose (UID, n=37) for 2years. The dose remained unchanged in 33 children initially randomized to receive a standard dose (FIX, 43 mu g/kg/day).We evaluated whether the variations in metabolic parameters measured during maintenance growth diminished in RID compared with UID or FIX.

    Results We observed less variation in fasting insulin levels (-50%), insulin sensitivity as assessed by homoeostasis model assessment (-55.1%), lean soft tissue (-27.8%) and bone mineral content (-31.3%) in RID compared with UID (all P<0.05), but no differences compared with FIX.

    Conclusions Continued reduced individualized GH treatment after the catch-up growth period is safe and reduces hyperinsulinism. Individualized GH dose can be reduced once the desired heightSDS is achieved to avoid overtreatment in terms of metabolic outcome.

  • 10. Decker, Ralph
    et al.
    Albertsson-Wikland, Kerstin
    Kriström, Berit
    Nierop, Andreas F. M.
    Gustafsson, Jan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Bosaeus, Ingvar
    Fors, Hans
    Hochberg, Ze'ev
    Dahlgren, Jovanna
    Metabolic outcome of GH treatment in prepubertal short children with and without classical GH deficiency2010In: Clinical Endocrinology, ISSN 0300-0664, E-ISSN 1365-2265, Vol. 73, no 3, p. 346-354Article in journal (Refereed)
    Abstract [en]

    P>Context Few studies have evaluated the metabolic outcomes of growth hormone (GH) treatment in idiopathic short stature (ISS). Moreover, children with ISS appear to need higher GH doses than children with GH deficiency (GHD) to achieve the same amount of growth and may therefore be at increased risk of adverse events during treatment. The individualized approach using prediction models for estimation of GH responsiveness, on the other hand, has the advantage of narrowing the range of growth response, avoiding too low or high GH doses. Design Short prepubertal children with either isolated GHD (39) or ISS (89) participated in a 2-year randomized trial of either individualized GH treatment with six different GH doses (range, 17-100 mu g/kg/day) or a standard dose (43 mu g/kg/day). Objective To evaluate if individualized GH treatment reduced the variance of the metabolic measures as shown for growth response and to compare changes in metabolic variables in children with ISS and GHD. Hypothesis Individualized GH dose reduces the range of metabolic outcomes, and metabolic outcomes are similar in children with ISS and GHD. Results We observed a narrower variation for fasting insulin (-34 center dot 2%) and for homoeostasis model assessment (HOMA) (-38 center dot 9%) after 2 years of individualized GH treatment in comparison with standard GH dose treatment. Similar metabolic changes were seen in ISS and GHD. Delta (delta) height SDS correlated with delta insulin-like growth factor I (IGF-I), delta leptin and delta body composition. Principal component analysis identified an anabolic and a lipolytic component. Anabolic variables [delta lean body mass (LBM) SDS and delta IGF-I SDS] clustered together and correlated strongly with delta height SDS and GH dose, whereas lipolytic variables [delta fat mass (FM) SDS and delta leptin] were clustered separately from anabolic variables. Regression analysis showed GH dose dependency in ISS, and to a lesser degree in GHD, for delta LBM SDS and delta height SDS, but not for changes in FM. Conclusions Individualized GH dosing during catch-up growth reduces the variance in insulin and HOMA and results in equal metabolic responses irrespective of the diagnosis of GHD or ISS.

  • 11.
    Derraik, Jose G. B.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health. Univ Auckland, Liggins Inst, Auckland, New Zealand;Univ Auckland, Better Start Natl Sci Challenge, Auckland, New Zealand.
    Miles, Harriet L.
    Univ Auckland, Liggins Inst, Auckland, New Zealand.
    Chiavaroli, Valentina
    Univ Auckland, Liggins Inst, Auckland, New Zealand.
    Hofman, Paul L.
    Univ Auckland, Liggins Inst, Auckland, New Zealand.
    Cutfield, Wayne S.
    Univ Auckland, Liggins Inst, Auckland, New Zealand;Univ Auckland, Better Start Natl Sci Challenge, Auckland, New Zealand.
    Idiopathic short stature and growth hormone sensitivity in prepubertal children2019In: Clinical Endocrinology, ISSN 0300-0664, E-ISSN 1365-2265, Vol. 91, no 1, p. 110-117Article in journal (Refereed)
    Abstract [en]

    Objective: We compared growth hormone sensitivity to an insulin-like growth factor I (IGF-I) generation test in children with idiopathic short stature (ISS) and of normal stature (NS) across the birthweight range.

    Methods: Forty-six prepubertal children (~7.1 years) born at term were studied: ISS (n = 23; 74% boys) and NS (n = 23; 57% boys). Children underwent a modified IGF-I generation test with recombinant human growth hormone (rhGH; 0.05 mg/kg/d) over four consecutive days. Hormonal concentrations were measured at baseline and day 5.

    Results: Children with idiopathic short stature were 1.90 SDS lighter (P < 0.0001) but had 4.5% more body fat (P = 0.0007) than NS children. Overall, decreasing birthweight SDS across the normal range (-1.9 to +1.5 SDS) was associated with lower percentage IGF-I response to rhGH stimulation in univariable (r = 0.45; P = 0.002) and multivariable models (β = 24.6; P = 0.006). Plasma IGF-I concentrations rose in both groups with rhGH stimulation (P < 0.0001). GHBP levels (P = 0.002) were suppressed in ISS children (-19%; P = 0.029) but increased among NS children (+18%; P = 0.028), with contrasting responses also observed for leptin and IGFBP-1. Further, the increase in insulin concentrations in response to rhGH stimulation was ~3-fold greater in NS children (142% vs 50%; P = 0.006).

    Conclusions: A progressive decrease in birthweight SDS was associated with a reduction in GH sensitivity in both NS and ISS children. Thus, the lower IGF-I response to rhGH stimulation in association with decreasing birthweight indicates that the ISS children at the lower end of the birthweight spectrum may have partial GH resistance, which may contribute to their poorer growth.

  • 12.
    Diakatou, Evanthia
    et al.
    G Gennimatas Athens Gen Hosp, Dept Pathol, Athens, Greece..
    Alexandraki, Krystallenia I.
    Univ Athens, Dept Pathophysiol, Athens, Greece..
    Tsolakis, Apostolos V.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrine Tumor Biology.
    Kontogeorgos, George
    G Gennimatas Athens Gen Hosp, Dept Pathol, Athens, Greece..
    Chatzellis, Eleftherios
    Univ Athens, Dept Pathophysiol, Athens, Greece..
    Leonti, Anastasia
    Alexandra Hosp, Dept Nucl Med, Athens, Greece..
    Kaltsas, Gregory A.
    Univ Athens, Dept Pathophysiol, Athens, Greece..
    Somatostatin and dopamine receptor expression in neuroendocrine neoplasms: correlation of immunohistochemical findings with somatostatin receptor scintigraphy visual scores2015In: Clinical Endocrinology, ISSN 0300-0664, E-ISSN 1365-2265, Vol. 83, no 3, p. 420-428Article in journal (Refereed)
    Abstract [en]

    ContextThe expression of somatostatin (sstr1-5) and dopamine (DR) receptors in neuroendocrine neoplasms (NENs) facilitates diagnosis by tumour visualization with somatostatin receptor scintigraphy (SRS) and directs towards specific treatment with peptide receptor radionuclide therapy (PRRT) with radiolabelled somatostatin analogues. ObjectiveTo investigate the co-expression of sstrs, D2R in relation to pre-operative SRSs in NENs. DesignProspective two-centre study. Patients and measurementsWe analysed pre-operative SRS of 60 patients [44 with gastrointestinal (GI) NENs and 16 with lung NENs] and compared SRS results with immunohistochemical (IHC) reactivity for sstr2, sstr3, sstr5 in sample tissues from primary (n=54) and metastatic (n=27) lesions and IHC reactivity for D2R in 23 samples from primary GI-NENs lesions. ResultsSstr2 was the commonest sstr expressed (654%) and was co-expressed with sstr3 and sstr5 in 321% and 247% of the specimens, respectively. In 67 of 81 specimens (827%), there was concordance of sstr2 immunohistochemistry with SRS findings (P<0001). D2R was expressed in only 8 of 23 (348%) GI-NENs while was co-expressed with sstr2 in all cases. SRS grade, as per Krenning scale, was higher in metastatic foci, large-size (>2cm) tumours and GI-NENs, whereas sstr2 intensity was greater in GI compared to lung NENs. SRS grade showed higher correlation with sstr2 (r=06, P<0001) and D2R (r=05, P<0001) IHC intensity scores than tumour size (r=04, P<0001) and sstr3 (r=04, P<0001) intensity score. ConclusionsSstr2 IHC expression and SRS are useful tools for the diagnosis and management of NENs because they display a high concordance. IHC expression of DR2 seems to be of potential clinical significance in GI-NENs tumours.

  • 13.
    Diderholm, Barbro
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health. Univ Cambridge, Addenbrookes Hosp NHS Fdn Trust, Dept Paediat, Cambridge, England..
    Beardsall, Kathryn
    Univ Cambridge, Addenbrookes Hosp NHS Fdn Trust, Dept Paediat, Cambridge, England..
    Murgatroyd, Peter
    Addenbrookes Hosp, Wellcome Trust Clin Res Facil, Cambridge, England..
    Lees, Christoph
    Rosie Matern Hosp, Dept Obstet & Gynaecol, Cambridge, England..
    Gustafsson, Jan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Dunger, David
    Univ Cambridge, Addenbrookes Hosp NHS Fdn Trust, Dept Paediat, Cambridge, England..
    Maternal rates of lipolysis and glucose production in late pregnancy are independently related to foetal weight2017In: Clinical Endocrinology, ISSN 0300-0664, E-ISSN 1365-2265, Vol. 87, no 3, p. 272-278Article in journal (Refereed)
    Abstract [en]

    Objective: Associations between maternal glucose levels and increased foetal growth are well established, and independent relationships with maternal weight, weight gain and insulin resistance are also observed. The relative roles of lipolysis and glucose production in the determination of these observations remain unclear. Design: We examined, through detailed physiological studies, the relationship between maternal late gestational energy substrate production (glucose and glycerol), maternal weight and weight gain, and estimated foetal size in the third trimester. Patients: Twenty-one nulliparous pregnant women, without gestational diabetes (GDM) assessed at 28 weeks with oral glucose tolerance test, were recruited. Measurements: Rates of hepatic glucose production (GPR) and rates of glycerol production (reflecting lipolysis) using [C-13(6)]-glucose and [H-2(5)]-glycerol were measured at 34-36 weeks of gestation. Respiratory quotient was assessed by indirect calorimetry and body composition by measurements of total body water (TBW; (H2O)-O-18) and body density (BODPOD). Foetal weight was estimated from ultrasound measures of biparietal diameter, femoral length and abdominal circumference. Results: At 34-36 weeks, bivariate analyses showed that GPR and lipolysis correlated with estimated foetal weight (r=.71 and .72, respectively) as well as with maternal weight, fat mass and fat-free mass, but not maternal weight gain. In multivariate analyses, rates of both glucose production (r=.42) and lipolysis (r=.47) were independently associated with foetal size explaining 63% of the variance. Conclusions: Both maternal rates of lipolysis and hepatic glucose production in late gestation are strongly related to estimated foetal weight.

  • 14.
    Ekeblad, Sara
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrine Tumor Biology.
    Lejonklou, Margareta Halin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrine Tumor Biology.
    Grimfjärd, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrine Tumor Biology.
    Johansson, Térèse
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrine Tumor Biology.
    Eriksson, Barbro
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrine Tumor Biology.
    Grimelius, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology.
    Stridsberg, Mats
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Biochemical endocrinology.
    Stålberg, Peter
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Skogseid, Britt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrine Tumor Biology.
    Co-expression of ghrelin and its receptor in pancreatic endocrine tumours2007In: Clinical Endocrinology, ISSN 0300-0664, E-ISSN 1365-2265, Vol. 66, no 1, p. 115-122Article in journal (Refereed)
    Abstract [en]

    Objective 

    Expression of ghrelin has been reported in pancreatic endocrine tumours, but data on ghrelin receptor protein expression are lacking. The aim of this study was to examine the ghrelin receptor, as well as ghrelin, in a selected series of these tumours, including multiple endocrine neoplasia 1 (MEN1) associated tumours, and to correlate data with clinical features including body mass index.

    Design 

    Immunohistochemical detection of ghrelin and its receptor was performed on frozen tissue from 31 tumours: 9 MEN1 and 22 sporadic. Twenty tumours were analysed by quantitative PCR. Plasma ghrelin was assessed in 26 patients.

    Results 

    Twenty-one (68%) of 31 tumours showed immunoreactivity for ghrelin (8/9 MEN1) and 19/20 expressed ghrelin mRNA. Ghrelin receptor protein was detected in 21/30 (70%) tumours (4/8 MEN1), and mRNA was detected in all analysed tumours. Insulinomas had significantly higher levels of receptor mRNA than other tumours. Five patients had elevated plasma ghrelin (> 2 SD above the control group mean). No significant difference in mean plasma ghrelin levels was found between patients (908 ± 569 ng/l) and controls (952 ± 164 ng/l). Mean BMI was 24·3 kg/m2. There was no association between ghrelin or receptor expression and survival.

    Conclusions 

    We report the first immunohistochemical data on expression of the ghrelin receptor in pancreatic endocrine tumours: 70% of tumours in our material. Concomitant ghrelin and receptor expression was seen in 50% of tumours, indicating an autocrine loop. Ghrelin was expressed in 68% of tumours (8/9 MEN1). Despite frequent ghrelin expression, elevated circulating ghrelin is rare in these patients.

  • 15. El-Mansoury, Mostafa
    et al.
    Berntorp, Kerstin
    Bryman, Inger
    Hanson, Charles
    Innala, Eva
    Karlsson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Landin-Wilhelmsen, Kerstin
    Elevated liver enzymes in Turner syndrome during a 5-year follow-up study2008In: Clinical Endocrinology, ISSN 0300-0664, E-ISSN 1365-2265, Vol. 68, no 3, p. 485-90Article in journal (Refereed)
    Abstract [en]

    OBJECTIVES: To study the prevalence and incidence of elevated liver enzymes and their relationship with body weight, metabolic factors and other diseases in Turner syndrome (TS). DESIGN: Five-year follow-up. PATIENTS: Women with TS (n = 218, mean age 33 +/- 13, range 16-71 years) from outpatient clinics at university hospitals in Sweden. MEASUREMENTS: Fasting blood samples for aspartate (AST) and alanine aminotransferase (ALT), bilirubin, alkaline phosphatase (ALP), gamma-glutamyl transferase (GT), viral hepatitis serology and hepatic auto-antibodies, vitamin B12, blood glucose, lipids and hormones. RESULTS: Seventy-nine subjects (36%) had one or more liver enzyme levels higher than the reference level, the most prevalent being GT. Karyotype 45,X was present in 51% of all TS women and in 48% of those with elevated liver enzymes. Body weight, body mass index (BMI), total cholesterol, triglycerides, and apolipoproteins A and B at start were higher in TS women with elevated liver enzymes than in TS women with normal levels. At 5 years, AST, ALT and GT were increased and another 23% of patients had developed elevated liver enzymes, that is, 59% in total (36% + 23%), while in 6%, the elevated liver enzymes had been normalized and all 6% also had lowered cholesterol levels. Multivariate analysis showed that GT was correlated with total cholesterol; P = 0.0032 at start and P = 0.0005 at 5 years, independently of other factors. Liver biopsy in six TS women showed one cholangitis, one hepatitis C, two steatosis and two normal biopsies. Withdrawal of oestrogen substitution did not influence the liver enzymes. CONCLUSIONS: Pathological liver enzymes were common in TS women, with a prevalence of 36% at 33 years of age, an annual incidence over 5 years of 3.4%. There was no relation to karyotype, alcohol, viral hepatitis, E(2) or autoimmunity, but a connection with total serum cholesterol.

  • 16. Evang, J Arild
    et al.
    Casar Borota, Olivera
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology. Dept. of laboratory medicine/pathology Umeå university hospital.
    Melum, Espen
    Holm, Ruth
    Ramm-Pettersen, Jon
    Bollerslev, Jens
    Berg, Jens P
    HDAC2 expression and variable number of repeats in exon 1 of the HDAC2 gene in corticotroph adenomas2010In: Clinical Endocrinology, ISSN 0300-0664, E-ISSN 1365-2265, Vol. 73, no 2, p. 229-235Article in journal (Refereed)
    Abstract [en]

    OBJECTIVES: Alterations in protein expression of histone deacetylase 2 (HDAC2) have been demonstrated in various neoplasms, and lack of nuclear expression of HDAC2 has previously been shown in some human and canine corticotroph adenomas. This study aimed to examine HDAC2 expression in a Norwegian cohort of corticotroph adenomas, screen for exonic HDAC2 gene variants in the adenomas and correlate the results with clinical data.

    PATIENTS AND DESIGN: Forty-four patients with verified Cushing's disease or Nelson's syndrome, positive ACTH staining and tissue available for immunohistochemistry and/or DNA sequencing were included. Ninety-four controls were chosen from the Norwegian Bone Marrow Registry.

    RESULTS: Histone deacetylase 2 expression examined by immunohistochemistry was strongly reduced in 3/30 adenomas. There were no association between HDAC2 expression and clinical variables. A previously unidentified insertion of three bases in a region coding for a polyserine cluster in exon 1 of the HDAC2 gene was identified in 6/32 adenomas. No other mutations in HDAC2 exons were found. Examination of DNA extracted from peripheral blood confirmed germ-line origin of the exon 1 insertion. The same insertion was also found in 28/94 of the controls (i.e., not significantly different from the patients).

    CONCLUSIONS: Strongly reduced HDAC2 protein expression was confirmed in a small portion of corticotroph tumours. Mutations in HDAC2 exons are unlikely to play an important role in the development of corticotroph adenomas.

  • 17. Evang, Johan Arild
    et al.
    Berg, Jens Petter
    Casar-Borota, Olivera
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology.
    Lekva, Tove
    Kringen, Marianne Kristiansen
    Ramm-Pettersen, Jon
    Bollerslev, Jens
    Reduced levels of E-cadherin correlate with progression of corticotroph pituitary tumours2011In: Clinical Endocrinology, ISSN 0300-0664, E-ISSN 1365-2265, Vol. 75, no 6, p. 811-818Article in journal (Refereed)
    Abstract [en]

    OBJECTIVES:

    Loss of E-cadherin is an important marker of epithelial tumour progression. The aims of this study were to explore whether E-cadherin expression and localization correlate to corticotroph tumour progression, relate the expression of the E-cadherin gene (CDH1) to immunohistochemical E-cadherin staining pattern, and study whether the E-cadherin levels were correlated to methylation status of the CDH1 promoter region.

    DESIGN:

    Immunohistochemical analyses of E-cadherin protein were performed, as was RT-qPCR of the CDH1 and the POMC genes. Methylation pattern of the promoter region of CDH1 was measured using pyrosequencing of bisulfite-treated DNA.

    PATIENTS:

    Forty-five patients operated at a tertiary referral centre in Oslo, Norway. Adenoma tissue sections and RNA samples from patients with verified Cushing's disease or Nelson's syndrome were collected.

    MEASUREMENTS:

    Expression of E-cadherin mRNA and protein in pituitary corticotroph adenomas and average percentage of methylated cytosines in a cytosine-phosphate-guanosine island of the CDH1 promoter.

    RESULTS:

    Correlations were observed between tumour progression and both nuclear expression of E-cadherin and reduced CDH1 mRNA. The E-cadherin expression was not determined by the methylation pattern of the CDH1 promoter.

    CONCLUSIONS:

    Corticotroph tumour progression was associated with reduced expression of the epithelial marker E-cadherin.

  • 18. Fougner, Stine L
    et al.
    Casar Borota, Olivera
    Oslo University.
    Berg, Jens Petter
    Hald, John K
    Ramm-Pettersen, Jon
    Bollerslev, Jens
    The clinical response to somatostatin analogues in acromegaly correlates to the somatostatin receptor subtype 2a protein expression of the adenoma.2008In: Clinical Endocrinology, ISSN 0300-0664, E-ISSN 1365-2265, Vol. 68, no 3, p. 458-65Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: Reduced expression of the somatostatin receptor subtype 2 (SSTR2) has been suggested as an explanation for the poor response to octreotide in acromegaly, but studies correlating levels of SSTR2 mRNA to octreotide efficacy have been contradictory. Some studies have found better responses to somatostatin analogues in G-protein alpha subunit (Gsalpha) mutation (gsp oncogene)-positive adenomas. The aim of this study was to determine adenoma SSTR2a protein expression and gsp status in a large group of patients with acromegaly, and relate this to the clinical effect of octreotide.

    PATIENTS: Seventy-one patients were included. All underwent transsphenoidal surgery, 23 patients after preoperative octreotide treatment.

    MEASUREMENTS: The adenoma SSTR2a expression was examined by immunohistochemistry and Western blot analysis, and gsp status determined. An acute octreotide test was performed, and the change in IGF-1 level after 6 months preoperative octreotide treatment was recorded.

    RESULTS: The acute octreotide response in non-pretreated patients and the preoperative long-term octreotide response were significantly better in patients with adenomas containing a large proportion of cells that stained positively for SSTR2a by immunohistochemistry. However, the SSTR2a protein level assessed by Western blot did not correlate with the octreotide response. The preoperatively treated group had lower SSTR2a protein levels and fewer adenomas with a large percentage of positively stained cells. The gsp oncogene was detected in 43% of the adenomas but did not correlate to the octreotide response.

    CONCLUSION: The clinical effect of octreotide correlates with the proportion of cells positive for SSTR2a in immunohistochemical staining, rather than the adenoma SSTR2a protein level. There may be a down-regulation of SSTR2a during octreotide treatment.

  • 19. Fougner, Stine Lyngvi
    et al.
    Casar-Borota, Olivera
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology.
    Heck, Ansgar
    Berg, Jens Petter
    Bollerslev, Jens
    Adenoma granulation pattern correlates with clinical variables and effect of somatostatin analogue treatment in a large series of patients with acromegaly2012In: Clinical Endocrinology, ISSN 0300-0664, E-ISSN 1365-2265, Vol. 76, no 1, p. 96-102Article in journal (Refereed)
    Abstract [en]

    CONTEXT:

    Somatotroph adenomas have been classified into densely granulated (DG) and sparsely granulated (SG) tumours with a transitional, intermediate group. Gsp oncogenes are activating mutations in the Gsα subunit gene, found in approximately 40% of somatotroph adenomas.

    OBJECTIVES:

    To explore granulation pattern and presence of gsp oncogene in acromegaly with correlations to clinical and biochemical variables and to the effect of treatment with somatostatin analogues (SA), as well as to describe granulation pattern in adenomas with and without SA pretreatment.

    DESIGN/SETTINGS/PATIENTS:

    Seventy-eight patients with active acromegaly were included. Long-term SA efficacy was evaluated in 29 patients treated preoperatively and in ten treated postoperatively. Granulation pattern was examined, as were immunohistochemical analyses for E-cadherin and SSTR2a. Protein levels of E-cadherin and SSTR2a were measured (Western blot). Gsp mutation analysis was available for 74 adenomas.

    RESULTS:

    DG adenomas and the transitional group had higher serum levels of IGF-1 per tumour volume than SG (P = 0·009; P = 0·005). Acute and long-term SA responses were lower in SG (P = 0·001; P = 0·043). No correlation between gsp mutation and granulation was found, and no difference in granulation pattern according to preoperative SA treatment was demonstrated. A significant correlation between granulation and E-cadherin was found, where SG had lowest immunohistochemical expression, substantiated by protein levels, and a highly significant gradient was observed from DG, through the transitional group, to SG.

    CONCLUSIONS:

    Densely granulated adenomas were highly responsive to somatostatin analogues in contrast to SG adenomas. The transitional group behaved clinically more like DG adenomas. However, based on E-cadherin, a marker of dedifferentiation, the transitional group seemed to be a true intermediate.

  • 20.
    Heather, Natasha L.
    et al.
    Auckland Dist Hlth Board, Newborn Metab Screening Programme, LabPlus, Auckland, New Zealand;Univ Auckland, Liggins Inst, Auckland, New Zealand.
    Derraik, Jose G. B.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health. Univ Auckland, Liggins Inst, Auckland, New Zealand.
    Webster, Dianne
    Auckland Dist Hlth Board, Newborn Metab Screening Programme, LabPlus, Auckland, New Zealand.
    Hofman, Paul L.
    Univ Auckland, Liggins Inst, Auckland, New Zealand;Auckland Dist Hlth Board, Starship Childrens Hosp, Auckland, New Zealand.
    The impact of demographic factors on newborn TSH levels and congenital hypothyroidism screening2019In: Clinical Endocrinology, ISSN 0300-0664, E-ISSN 1365-2265, Vol. 91, no 3, p. 456-463Article in journal (Refereed)
    Abstract [en]

    Context

    Optimal newborn screening thyroid‐stimulating hormone (TSH) cut‐offs are contentious. Analysis of demographic factors that impact screen TSH levels may help explain international variance and provide guidance to screening programmes.

    Objective

    To determine the influence of demographic factors on newborn screening TSH levels and screening performance parameters.

    Design and Setting

    National, retrospective population study using blood spot TSH cards from the New Zealand newborn screening programme in 2010‐2015.

    Patients

    325 685 blood spot cards.

    Main Outcome Measures

    Likelihood of exceeding specific TSH thresholds (TSH ≥5, ≥10 and ≥15 mIU/L) and group‐specific screening performance parameters.

    Results

    The likelihood of high TSH levels differed between ethnic groups. Pacific Island infants were more than twice as likely to have high‐normal TSH levels (≥5 and ≥10 mIU/L) and nearly twice as likely to have a positive screen (≥15 mIU/L) as New Zealand Europeans. Māori or Chinese ethnicity, male sex, younger gestational age and greater socio‐economic deprivation scores were also associated with high‐normal TSH levels. At a TSH threshold ≥15 mIU/L, screening sensitivity was lowest (88.89% vs 95.83% overall) and PPV greatest (88.89% vs 62.84%) amongst Asian infants. Early samples were more than three times as likely to reach the screen‐positive threshold and more likely to yield a false‐positive result (PPV 20.00% vs 68.87%, P = 0.004).

    Conclusions

    Newborn TSH levels are impacted by a number of demographic variables, particularly ethnicity and age at sample collection. Screening performance may be improved through the use of targeted thresholds.

  • 21. Heck, Ansgar
    et al.
    Ringstad, Geir
    Fougner, Stine L.
    Casar-Borota, Olivera
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology.
    Nome, Terje
    Ramm-Pettersen, Jon
    Bollerslev, Jens
    Intensity of pituitary adenoma on T2-weighted magnetic resonance imaging predicts the response to octreotide treatment in newly diagnosed acromegaly2012In: Clinical Endocrinology, ISSN 0300-0664, E-ISSN 1365-2265, Vol. 77, no 1, p. 72-78Article in journal (Refereed)
    Abstract [en]

    Background Primary, preoperative medical treatment is an option in selected patients with acromegaly, but a subset of patients respond poorly. Valid prediction of response to somatostatin analogues (SA) might thus alter treatment stratification. The aims of this study were to assess whether T2 signal intensity could determine long-term response to first-line SA treatment and to assess clinical and biochemical baseline characteristics, as well as histological subtype in relation to the magnetic resonance imaging (MRI) appearances. Methods In 45 newly diagnosed patients, T2-weighted signal intensity of the tumour was classified into hypo-, iso- or hyperintense. Biochemical and clinical baseline variables for the three groups were compared. In 25 patients primarily treated with long-acting SA for a median of 6 months [interquartile range (IQR):155180 days], GH and IGF-1 reduction was assessed, and in 34 cases, immunohistochemical granulation pattern was evaluated. Results The results showed that 12 (27%) adenomas were hypointense, 15 (33%) isointense and 18 (40%) hyperintense. Median IGF-1 [ratio IGF-1/ULN; (upper limit of normal)] was 3.5 (2.34.9), 2.9 (2.63.8) and 1.9 (1.32.6), respectively (P = 0.006 for difference between groups). Median GH values (mu g/l) of a 3- to 5-point profile were 17.5 (6.135), 9.3 (6.032.5) and 4.1 (1.58.3), (P = 0.025). Median IGF-1 reduction (% of baseline) after first-line SA treatment was 51 (4970), 36 (1974) and 13 (542) (P = 0.03); median reduction in GH (% of baseline) was 86 (7294), 78 (6285) and 46 (170) (P = 0.02). T2 hyperintensity was associated with sparse granulation pattern on immunohistochemistry. Conclusion In patients with acromegaly, T2 signal intensity at diagnosis correlates with histological features and predicts biochemical outcome of first-line SA treatment.

  • 22.
    Hong, Ye
    et al.
    Zhejiang Univ, Sch Med, Childrens Hosp, Endocrinol Dept, Hangzhou, Zhejiang, Peoples R China.
    Maessen, Sarah E.
    Univ Auckland, Liggins Inst, Auckland, New Zealand.
    Dong, Guanping
    Zhejiang Univ, Sch Med, Childrens Hosp, Endocrinol Dept, Hangzhou, Zhejiang, Peoples R China.
    Huang, Ke
    Zhejiang Univ, Sch Med, Childrens Hosp, Endocrinol Dept, Hangzhou, Zhejiang, Peoples R China.
    Wu, Wei
    Zhejiang Univ, Sch Med, Childrens Hosp, Endocrinol Dept, Hangzhou, Zhejiang, Peoples R China.
    Liang, Li
    Zhejiang Univ, Affiliated Hosp 1, Dept Pediat, Sch Med, Hangzhou, Peoples R China.
    Wang, Chun Lin
    Zhejiang Univ, Affiliated Hosp 1, Dept Pediat, Sch Med, Hangzhou, Peoples R China.
    Chen, Xiaochun
    Zhejiang Univ, Sch Med, Childrens Hosp, Endocrinol Dept, Hangzhou, Zhejiang, Peoples R China.
    Gibbins, John D.
    Univ Auckland, Liggins Inst, Auckland, New Zealand.
    Cutfield, Wayne S.
    Univ Auckland, Liggins Inst, Auckland, New Zealand;Univ Auckland, A Better Start Natl Sci Challenge, Auckland, New Zealand.
    Derraik, Jose G. B.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health. Zhejiang Univ, Sch Med, Childrens Hosp, Endocrinol Dept, Hangzhou, Zhejiang, Peoples R China;Univ Auckland, Liggins Inst, Auckland, New Zealand;Univ Auckland, A Better Start Natl Sci Challenge, Auckland, New Zealand.
    Fu, JunFen
    Zhejiang Univ, Sch Med, Childrens Hosp, Endocrinol Dept, Hangzhou, Zhejiang, Peoples R China.
    Associations between maternal age at menarche and anthropometric and metabolic parameters in the adolescent offspring2019In: Clinical Endocrinology, ISSN 0300-0664, E-ISSN 1365-2265, Vol. 90, no 5, p. 702-710Article in journal (Refereed)
    Abstract [en]

    Objective: We examined the associations between maternal age at menarche and anthropometry and metabolism in adolescent offspring.

    Methods: Anthropometric, metabolic and blood pressure data were obtained from 304 girls and 190 boys aged 11-16 years attending school in Hangzhou (China). Age at menarche for both mothers and daughters was self-reported. Fasting blood samples were obtained and all participants underwent clinical examinations. Obesity was defined as BMI >= 95th percentile for age and sex.

    Results: Older maternal age at menarche was associated with older age of their daughters at menarche (r = 0.21; P < 0.001). Mother's age at menarche was not associated with anthropometry or metabolism of daughters. However, younger maternal age at menarche was associated with increased hip and waist circumferences, and BMI SDS of their sons. Boys whose mothers were <= 13 years at menarche had an adjusted relative risk of obesity 3-fold greater than sons of mothers with a later menarcheal onset (2.96; 95% CI 1.49, 5.87). Among daughters, every 1-year increase in their age at menarche was associated with a 0.34 SDS reduction in BMI. Increasing age at menarche was also associated with reduced waist and hip circumferences (-1.5 and -1.8 cm/y, respectively) and waist-to-height ratio (-0.008 per year). Girls in the youngest menarcheal age tertile (8.8-11.6 years) had diastolic blood pressure 2.2 mm Hg higher than other girls (P = 0.029).

    Conclusions: Younger maternal age at menarche is associated with increased obesity risk in their sons, but not daughters. However, girls who experience menarche earlier have a less favourable anthropometric profile.

  • 23. Johannsson, Gudmundur
    et al.
    Falorni, Alberto
    Skrtic, Stanko
    Lennernäs, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Quinkler, Marcus
    Monson, John P.
    Stewart, Paul M.
    Adrenal insufficiency: review of clinical outcomes with current glucocorticoid replacement therapy2015In: Clinical Endocrinology, ISSN 0300-0664, E-ISSN 1365-2265, Vol. 82, no 1, p. 2-11Article, review/survey (Refereed)
    Abstract [en]

    Glucocorticoid replacement therapy in patients with adrenal insufficiency (AI), whether primary (Addison's disease) or secondary (due to hypopituitarism), has been established for some 50years. The current standard treatment regimen involves twice- or thrice-daily dosing with a glucocorticoid, most commonly oral hydrocortisone. Based on previous small-scale studies and clinical perception, life expectancy with conventional glucocorticoid replacement therapy has been considered normal, with a low incidence of adverse events. Data from the past 10-15years, however, have shown that morbidity remains high and life expectancy is reduced. The increased morbidity and decreased life expectancy appear to be due to both increased exposure to cortisol and insufficient cortisol coverage during infections and other stress-related events. This is thought to reflect a failure of treatment to replicate the natural circadian rhythm of cortisol release, together with a failure to identify and deliver individualized cortisol exposure and to manage patients adequately when increased doses are required. The resulting over- or under-treatment may result in Cushing-like symptoms or adrenal crisis, respectively. This review summarizes the morbidity and mortality seen in patients receiving the current standard of care for AI and suggests areas for improvement in glucocorticoid replacement therapy.

  • 24. Kaltsas, Gregory
    et al.
    Grozinsky-Glasberg, Simona
    Alexandraki, Krystallenia I.
    Thomas, Dimitrios
    Tsolakis, Apostolos V.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrine Tumor Biology.
    Gross, David
    Grossman, Ashley B.
    Current concepts in the diagnosis and management of type 1 gastric neuroendocrine neoplasms2014In: Clinical Endocrinology, ISSN 0300-0664, E-ISSN 1365-2265, Vol. 81, no 2, p. 157-168Article, review/survey (Refereed)
    Abstract [en]

    The vast majority of gastrin-related gastrointestinal neuroendocrine neoplasms (GI-NENs) develop in the context of chronic atrophic gastritis (type 1), a condition closely related to autoimmune thyroid diseases. These neoplasms are defined as gastric NENs type 1 (GNEN1) and have recently been shown to constitute the commonest GI-NENs in a prospective study. GNEN1s are usually multiple and follow a relative indolent course, raising questions regarding the extent that such patients should be investigated and the appropriate therapeutic interventions needed. Recently, a number of consensus statements and guidelines have been published from various societies dealing with the diagnosis and management of GI-NENs. Endocrinologists are among the many different medical specialties involved in GNEN1s diagnosis and management. However, despite recent advances, few randomized trials are available, and thus existing evidence remains relatively weak compared to other malignancies. The purpose of this review is to provide recent evidence along with currently employed modalities addressing the diagnosis, management, long-term follow-up and potential comorbidities of GNEN1s.

  • 25.
    Kołtowska-Häggström, Maria
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Kind, Paul
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Monson, John P
    Jonsson, Björn
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Growth hormone replacement in hypopituitary adults with growth hormone deficiency evaluated by a utility-weighted quality of life index: a precursor to cost-utility analysis2007In: Clinical Endocrinology, ISSN 0300-0664, E-ISSN 1365-2265, Vol. 68, no 1, p. 122-129Article in journal (Refereed)
    Abstract [en]

    Objectives To examine quality of life (QoL) measured by a utility-weighted index in GH-deficient adults on GH replacement and analyse the impact of demographic and clinical characteristics on changes in utilities during treatment. Design Utilities for items in the QoL-Assessment of Growth Hormone Deficiency in Adults (QoL-AGHDAutility) were estimated based on data obtained from the general population in England and Wales (E&W). These estimates were used to calculate QoL changes in GH-treated patients and compare these with normative population values. Patients A total of 894 KIMS patients (53% women) from E&W were followed for 1 to 6 years. Measurements QoL-AGHDAutility at baseline and at the last reported visit, total QoL-AGHDAutility gain and QoL-AGHDAutility gain per year of follow-up. Results QoL-AGHDAutility in patients before GH treatment differed from the expected population values [0·67 (SD 0·174) vs. 0·85 (SD 0-038),P < 0·0001], constituting a mean deficit of -0·19 (SD 0·168). There was a difference in the mean QoL-AGHDAutility deficit for men [-0·16 (SD 0-170)] and women [-0·21 (SD 0-162)] (P < 0·001). The main improvement occurred during the first year of treatment [reduction of a deficit to -0·07 (SD 0·163) (P < 0·001) in the total cohort]; however, patients' utilities remained lower than those recorded for the general population during subsequent follow-up (P < 0·001). Despite an observed impact of age, primary aetiology, disease onset and comorbidities on QoL-AGHDAutility, all patients showed a similar beneficial response to treatment. Conclusions QoL-AGHDAutility efficiently monitors treatment effects in patients with GHD. The study confirmed the QoL-AGHDAutility deficit before treatment and a similar QoL-AGHDAutility gain observed after commencement of GH replacement in all patients.

  • 26.
    Leong, Karen S. W.
    et al.
    Univ Auckland, Liggins Inst, Auckland, New Zealand..
    Derraik, Jose G. B.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health. Univ Auckland, Liggins Inst, Auckland, New Zealand.;Univ Auckland, Better Start Natl Sci Challenge, Auckland, New Zealand..
    Hofman, Paul L.
    Univ Auckland, Liggins Inst, Auckland, New Zealand..
    Cutfield, Wayne S.
    Univ Auckland, Liggins Inst, Auckland, New Zealand.;Univ Auckland, Better Start Natl Sci Challenge, Auckland, New Zealand..
    Antibiotics, gut microbiome and obesity2018In: Clinical Endocrinology, ISSN 0300-0664, E-ISSN 1365-2265, Vol. 88, no 2, p. 185-200Article, review/survey (Refereed)
    Abstract [en]

    Antibiotics have been hailed by many as "miracle drugs" that have been effectively treating infectious diseases for over a century, leading to a marked reduction in morbidity and mortality. However, with the increasing use of antibiotics, we are now faced not only with the increasing threat of antibiotic resistance, but also with a rising concern about potential long-term effects of antibiotics on human health, including the development of obesity. The obesity pandemic continues to increase, a problem that affects both adults and children alike. Disruptions to the gut microbiome have been linked to a multitude of adverse conditions, including obesity, type 2 diabetes, inflammatory bowel diseases, anxiety, autism, allergies, and autoimmune diseases. This review focuses on the association between antibiotics and obesity, and the role of the gut microbiome. There is strong evidence supporting the role of antibiotics in the development of obesity in well-controlled animal models. However, evidence for this link in humans is still inconclusive, and we need further well-designed clinical trials to clarify this association.

  • 27.
    Lindberg, Daniel
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Åkerström, Göran
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Westin, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Evaluation of CDKN2C/p18, CDKN1B/p27 and CDKN2B/p15 mRNA expression and CpG methylation status in sporadic and MEN1-associated pancreatic endocrine tumors.2008In: Clinical Endocrinology, ISSN 0300-0664, E-ISSN 1365-2265, Vol. 68, p. 271-277Article in journal (Refereed)
  • 28.
    Lindberg, Daniel
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Åkerström, Göran
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Westin, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Evaluation of CDKN2C/p18, CDKN1B/p27, and CDKN2B/p15 mRNA expression and CpG methylation status in sporadic and MEN1-associated pancreatic endocrine tumors2008In: Clinical Endocrinology, ISSN 0300-0664, E-ISSN 1365-2265, Vol. 68, no 2, p. 271-278Article in journal (Refereed)
    Abstract [en]

    Objective Menin, encoded by the multiple endocrine neoplasia type 1 (MEN1) gene at 11q13, enhances transcription of the cyclin-dependent kinase inhibitors (CDIs), CDKN2C (p18) and CDKN1B (p27) in mouse pancreatic islets, and inactivation of menin reduced CDKN2B (p15) expression in this mouse model. Here, we have compared the relative mRNA expression level and CpG methylation status of p18, p27 and p15 in 18 pancreatic endocrine tumours (PETs) with or without MEN1 gene mutations. Design Real-time quantitative PCR, DNA sequencing and pyro-sequencing methylation analysis were employed. Results The p18 gene was expressed in 15 out of the 18 analysed PETs. The expression level was within the range of the normal pancreatic tissues or higher. Of the three remaining tumours with no expression, two displayed loss of heterozygocity (LOH) at 11q13, one derived from a MEN1 patient. The p27 gene was expressed in all PETs at a level higher than the normal pancreatic tissues, except for one tumour. Promoter methylation was not detected for p18 and p27. p15 expression was undetectable in 8/18 (44%) of the PETs, and no general relations to tumour syndrome, malignancy or MEN1 gene mutations were evident. This was not due to homozygous gene deletions, but the p15 promoter was hypermethylated in two insulinomas. No mutations were found in the pl5 gene. Conclusions Expression of p15, p18 and p27 was not generally related to the MEN1 gene mutational status of the investigated 18 PETs. The p15 gene was silenced by promoter hypermethylation in two tumours. Dysregulation of menin and the CDIs are important in PET tumorigenesis, and their interrelations remain to be elucidated.

  • 29.
    Lindberg, Daniel
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Åkerström, Göran
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Westin, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Mutational analyses of WNT7A and HDAC11 as candidate tumor suppressor genes in sporadic malignant pancreatic endocrine tumors.2007In: Clinical Endocrinology, ISSN 0300-0664, E-ISSN 1365-2265, Vol. 66, p. 110-114Article in journal (Refereed)
  • 30.
    Lindberg, Daniel
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Åkerström, Göran
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Westin, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Mutational analyses of WNT7A and HDAC11 as candidate tumour suppressor genes in sporadic malignant pancreatic endocrine tumours2007In: Clinical Endocrinology, ISSN 0300-0664, E-ISSN 1365-2265, Vol. 66, no 1, p. 110-114Article in journal (Refereed)
    Abstract [en]

    Objective We and others have reported loss of heterozygosity (LOH) on chromosome 3p25 in sporadic malignant pancreatic endocrine tumours (PETs). A common region of deletion on chromosome 3p25 contains numerous genes, including VHL and PPARγ, that have been excluded previously as candidate tumour suppressor genes by DNA sequencing analysis. We have analysed whether WNT7A or HDAC11 was biallelically inactivated in a group of well-characterized PETs.

    Patients and design Ten PETs from eight patients were selected from a previous study, where LOH on chromosome 3p25 was found in 11 out of 22 sporadic PETs. These tumours were examined for inactivating mutations of WNT7A and HDAC11 by direct sequencing of all exons and intron–exon boundaries. Inactivation of WNT7A expression by aberrant CpG island methylation and WNT7A protein expression were evaluated by methylation-specific polymerase chain reaction (PCR) and immunohistochemistry, respectively. HDAC11 protein expression was also examined.

    Results No point mutations, deletion or insertions were detected in either WNT7A or HDAC11 in any of the PETs. Two polymorphisms were identified in the third exon of the WNT7A gene. CpG methylation of the WNT7A gene was not detected and the WNT7A and HDAC11 proteins were normally expressed.

    Conclusion The absence of tumour-specific somatic events in WNT7A and HDAC11 suggests that these genes are unlikely to have a classical tumour suppressor gene role in sporadic malignant PETs. The putative 3p25 tumour suppressor remains to be identified.

  • 31. Lindmark, S
    et al.
    Burén, J
    Eriksson, Jan W
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrinology, Diabetes and Metabolism.
    Insulin resistance, endocrine function and adipokines in type 2 diabetes patients at different glycaemic levels: potential impact for glucotoxicity in vivo.2006In: Clinical Endocrinology, ISSN 0300-0664, E-ISSN 1365-2265, Vol. 65, no 3, p. 301-9Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: To evaluate the interplay between hyperglycaemia, insulin resistance, hormones and adipokines in patients with type 2 diabetes mellitus (T2DM).

    DESIGN AND METHODS: Ten patients with T2DM with good glycaemic control (G), 10 with poor control (P) and 10 nondiabetic control subjects (C) were matched for sex (M/F 6/4), age and body mass index. A hyperinsulinaemic, euglycaemic clamp was performed and cytokines and endocrine functions, including cortisol axis activity were assessed.

    RESULTS: Patients with diabetes were more insulin resistant than group C, and group P exhibited the highest degree of insulin resistance (P = 0.01, P vs C). Tumour necrosis factor (TNF)-alpha levels were elevated in patients with diabetes (P = 0.05) and group P had the highest levels of fasting serum cortisol (P = 0.05), nonesterified fatty acids (NEFA; P = 0.06) and C-reactive protein (CRP; P = 0.01). Adiponectin levels were lower in the P group. In partial correlation analyses, significant associations were found: glycaemic level (HbA1c) with insulin resistance, TNF-alpha, CRP and basal and ACTH-stimulated cortisol levels, insulin resistance with plasma NEFA, TNF-alpha and stimulated cortisol levels.

    CONCLUSION: Poor glycaemic control in patients with T2DM was associated with insulin resistance and with elevated TNF-alpha, CRP and basal as well as stimulated cortisol levels. Inflammatory mediators, e.g. TNF-alpha, may contribute to insulin resistance in hyperglycaemic patients with T2DM and this might be a partial explanation for glucotoxicity.

  • 32.
    Lingaiah, Shilpa
    et al.
    Oulu Univ Hosp, Dept Obstet & Gynaecol, PEDEGO Res Unit, Med Res Ctr, Oulu, Finland.;Univ Oulu, Oulu, Finland..
    Morin-Papunen, Laure
    Oulu Univ Hosp, Dept Obstet & Gynaecol, PEDEGO Res Unit, Med Res Ctr, Oulu, Finland.;Univ Oulu, Oulu, Finland..
    Piltonen, Terhi
    Oulu Univ Hosp, Dept Obstet & Gynaecol, PEDEGO Res Unit, Med Res Ctr, Oulu, Finland.;Univ Oulu, Oulu, Finland..
    Puurunen, Johanna
    Oulu Univ Hosp, Dept Obstet & Gynaecol, PEDEGO Res Unit, Med Res Ctr, Oulu, Finland.;Univ Oulu, Oulu, Finland..
    Sundström Poromaa, Inger
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Research group (Dept. of women´s and children´s health), Reproductive Health.
    Stener-Victorin, Elisabet
    Karolinska Inst, Dept Physiol & Pharmacol, Stockholm, Sweden..
    Bloigu, Risto
    Univ Oulu, Med Informat & Stat Res Grp, Oulu, Finland..
    Risteli, Juha
    Oulu Univ Hosp, Dept Clin Chem, Oulu, Finland..
    Tapanainen, Juha S.
    Oulu Univ Hosp, Dept Obstet & Gynaecol, PEDEGO Res Unit, Med Res Ctr, Oulu, Finland.;Univ Oulu, Oulu, Finland.;Univ Helsinki, Dept Obstet & Gynaecol, Helsinki, Finland.;Helsinki Univ Hosp, Helsinki, Finland..
    Bone markers in polycystic ovary syndrome: A multicentre study2017In: Clinical Endocrinology, ISSN 0300-0664, E-ISSN 1365-2265, Vol. 87, no 6, p. 673-679Article in journal (Refereed)
    Abstract [en]

    Objective: Hyperandrogenism, hyperinsulinaemia and obesity, known characteristics of polycystic ovary syndrome (PCOS), may influence bone mineral density and biochemical markers of bone turnover (BTMs) can provide a noninvasive assessment of bone turnover. To this end, the serum concentrations of BTMs and 25-hydroxyvitamin D (25OHD) were analysed in women with PCOS, and their possible associations with metabolic parameters of PCOS were determined.

    Subjects and methods: Bone formation markers procollagen type I amino-terminal propeptide (PINP) and osteocalcin (OC), and bone resorption marker carboxy-terminal cross-linking telopeptide of type I collagen (CTX), along with 25OHD, were measured in 298 women with PCOS and 194 healthy controls.

    Results: Serum levels of PINP (47.020.2 vs 58.1 +/- 28.6g/L, P<.001) and OC (18.2 +/- 7.5 vs 20.6 +/- 9.8g/L, P<.001) were decreased in women with PCOS compared with controls, whereas no significant differences were found in CTX and 25OHD levels. Age-stratified analyses suggested that PINP (50.5 +/- 21.7 vs 68.2 +/- 26.6g/L, P<.001) and OC levels (20.4 +/- 7.6 vs 25.5 +/- 9.6g/L, P<.001) were decreased only in the younger age group (30years) women with PCOS compared with controls. The formation markers and resorption marker decreased with age in both study groups.

    Conclusions: Bone formation markers were decreased in younger women with PCOS when compared with healthy women, which may affect bone mass in these women.

  • 33.
    Mitra, M. Tanya
    et al.
    Guys & St Thomas NHS Fdn Trust, Evelina London Childrens Hosp, London, England..
    Jonsson, Peter
    Pfizer Endocrine Care, Sollentuna, Sweden..
    Akerblad, Ann-Charlotte
    Pfizer Endocrine Care, Sollentuna, Sweden..
    Clayton, Peter
    Royal Manchester Childrens Hosp, Manchester Acad Hlth Sci Ctr, Manchester, Lancs, England..
    Koltowska-Häggström, Maria
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Korbonits, Marta
    Queen Mary Univ London, Barts & London Sch Med, London, England..
    Toogood, Andy
    Queen Elizabeth Hosp, Dept Endocrinol, Birmingham B15 2WB, W Midlands, England..
    Gleeson, Helena
    Queen Elizabeth Hosp, Dept Endocrinol, Birmingham B15 2WB, W Midlands, England..
    Social, educational and vocational outcomes in patients with childhood-onset and young-adult-onset growth hormone deficiency2017In: Clinical Endocrinology, ISSN 0300-0664, E-ISSN 1365-2265, Vol. 86, no 4, p. 526-533Article in journal (Refereed)
    Abstract [en]

    Objective Hypopituitarism diagnosed in childhood, adolescence and young adulthood has the potential to affect growth and somatic development. Less is known about the impact of such a diagnosis on other aspects of development. Design An analysis of the KIMS database (Pfizer International Metabolic Database) was performed to explore social, educational and vocational outcomes of adult patients diagnosed in childhood, adolescence and young adulthood compared with adult-onset controls. Patients A total of 2952 adult patients diagnosed with hypothalamic pituitary conditions before the age of 25 were divided into two groups: childhood-onset [<16 years (CO)] (n = 1782) and young-adult-onset [16 to <25 years (YAO)] (n = 1170). A total of 1617 adult patients diagnosed with a nonfunctioning pituitary adenoma at the age of 25 or older formed the adult-onset control group (AO). Measurements KIMS Patient Life Situation Form which provided information on social, educational and vocational outcomes. Results Compared with the AO control group, CO and YAO patients were between 45 and 80 times more likely to live with their parents in adulthood; CO and YAO patients were also less likely to live in partnership and to have children. The impact on educational and vocational outcomes was less marked than on social outcomes with no significant differences compared with the AO control group. Educational and vocational outcomes showed the lowest level in male and female CO and YAO patients who had been previously diagnosed with a brain tumour. ConclusionsSocial outcomes were more affected than educational and vocational outcomes. Although CO patients are more adversely affected, YAO patients were also failing to achieve social milestones. This has consequences for the delivery of endocrine care in both paediatric and adult services.

  • 34. Monson, John P.
    et al.
    Jönsson, Peter
    Koltowska-Häggström, Maria
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Kourides, Ione
    Growth hormone (GH) replacement decreases serum total and LDL-cholesterol in hypopituitary patients on maintenance HMG CoA reductase inhibitor (statin) therapy2007In: Clinical Endocrinology, ISSN 0300-0664, E-ISSN 1365-2265, Vol. 67, no 4, p. 623-628Article in journal (Refereed)
    Abstract [en]

    Objective Adult onset GH deficiency (GHD) is characterized by abnormalities of serum lipoprotein profiles and GH replacement results in favourable alterations in serum total and low density lipoprotein (LDL)-cholesterol. Preliminary evidence has indicated that the effect of GH replacement in this respect may be additive to that of HMG CoA reductase inhibitor (statin) therapy. We have examined this possibility during prospective follow-up of adult onset hypopituitary patients enrolled in KIMS (Pfizer International Metabolic Database), a pharmacoepidemiological study of GH replacement in adult hypopituitary patients. Design Lipoprotein profiles were measured centrally at baseline and after 12 months GH replacement therapy. Patients Sixty-one hypopituitary patients (30 male, 31 female) on maintenance statin therapy (mean 2·5 ± 2·7 SD years before GH) (statin group - SG) and 1247 (608 male, 639 female) patients not on hypolipidaemic therapy (nonstatin group - NSG) were studied. All patients were naive or had not received GH replacement during the 6 months prior to study. Patients who developed diabetes mellitus during the first year of GH therapy or in the subsequent year and those with childhood onset GHD were excluded from this analysis. An established diagnosis of diabetes mellitus was present in 18% SG and 4·4% NSG at baseline. Measurements Serum concentrations of total, high density lipoprotein (HDL)-cholesterol, triglycerides and IGF-I were measured centrally in all patients and LDL-cholesterol was estimated using Friedewald's formula. Results The relative frequency of various statin use was simvastatin 52% (15·8 ± 8-1 mg, mean ± SD), atorvastatin 30% (14·4 ± 7·8 mg), pravastatin 9·8% (31·6 mg ± 13-9 mg), lovastatin 6·6% (17·5 ± 5 mg) and fluvastatin 1·6% (40 mg). Baseline serum total and LDL-cholesterol (mean ± SD) were 5·2 ±1-4 and 3·1 ± 1·3 mmol/l in SG and 5·8 ± 1·2 and 3-7 ± 1·0 mmol/l in NSG, respectively (P < 0·0001, SG vs. NSG).After 12 months GH replacement (SG: 0·32 ±0·17 mg/day; NSG: 0-38 ± 0·1 mg/day) serum total and LDL-cholesterol decreased by a mean (±SD) of 0·48 (± 1·25) mmol/l (P< 0-0004) and 0-53 (±1·08) mmol/l (P< 0·0001) in SG and by 0·30 (± 0·89) mmol/l (P<0·0001) and 0-28 (± 0·80) mmol/l (P<0·0001) in NSG, respectively. There were no significant changes in HDL-cholesterol or triglycerides in either group (SG vs. NSG: NS). A relationship between LDL-cholesterol at baseline and the decrease in LDL-cholesterol after 12 months GH was evident in both groups (SG: R=-0·54, P< 0·001; NSG: R=-0·4, P< 0·001) and a similar relationship for cholesterol was observed. Conclusions These data indicate that GH replacement exerts additional beneficial effects on lipoprotein profiles in patients on maintenance statin therapy, confirming that the effects of these interventions are complementary rather than exclusive.

  • 35.
    Nybacka, Åsa
    et al.
    Karolinska Inst, Div Obstet & Gynecol, Dept Womens & Childrens Hlth, Stockholm, Sweden.;Karolinska Univ Hosp, Dept Obstet & Gynecol, Stockholm, Sweden.;Karolinska Univ Hosp, Dept Clin Nutr & Dietet, Stockholm, Sweden..
    Hellström, Per M.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Gastroenterology/Hepatology.
    Hirschberg, Angelica L.
    Karolinska Inst, Div Obstet & Gynecol, Dept Womens & Childrens Hlth, Stockholm, Sweden.;Karolinska Univ Hosp, Dept Obstet & Gynecol, Stockholm, Sweden..
    Increased fibre and reduced trans fatty acid intake are primary predictors of metabolic improvement in overweight polycystic ovary syndromeSubstudy of randomized trial between diet, exercise and diet plus exercise for weight control2017In: Clinical Endocrinology, ISSN 0300-0664, E-ISSN 1365-2265, Vol. 87, no 6, p. 680-688Article in journal (Refereed)
    Abstract [en]

     Objective: Polycystic ovary syndrome (PCOS) is commonly affected by obesity. PCOS phenotypes are prone to increased waist/hip ratio, insulin resistance and dyslipidaemia. This substudy was undertaken to evaluate the effects of lifestyle interventions on metabolic biomarkers in overweight/obese PCOS women and the interventional effects of dietary components related to metabolic outcomes.

    Design: Randomized three-arm parallel study.

    Patients: Fifty-seven PCOS women body mass index (BMI >27kg/m(2), age 18-40) were randomly assigned to diet (D, n=19), exercise (E, n=19) or diet plus exercise (DE, n=19) in three-arm fashion over 16weeks. The D group received nutritional counselling by a dietician to reduce their energy intake by at least 600kcal/d. The E group received an ambulatory exercise regimen from a physiotherapist. The DE group had both interventions.

    Measurements: Self-reported food intake over 4days, exercise pedometers, BMI, waist/hip ratio, blood pressure, body composition and oral glucose tolerance test were performed before and at the end of intervention.

    Results: BMI, waist circumference and total cholesterol were significantly reduced in the D and DE groups, as well as low-density lipoprotein and Homeostasis Model of Assessment index in the D group. In the E group, exercise was increased along with a decrease in BMI and waist circumference. The strongest predictor of reduced BMI was increased fibre intake (-0.44, P=.03), while a decrease in trans fatty acid intake predicted reduced insulinogenic index (0.44, P<.01).

    Conclusions: Nutritional counselling with dieting is clearly effective to improve metabolic disturbances in overweight/obese women with PCOS. Increased fibre and reduced trans fatty acid intake are primary predictors of metabolic improvement and weight control.

  • 36.
    Petridou, Eleni
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Mantzoros, Christos S
    Belechri, Maria
    Skalkidou, Alkistis
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Dessypris, Nick
    Papathoma, Eugenia
    Salvanos, Heraklis
    Lee, Jennifer H
    Kedikoglou, Simeon
    Chrousos, George
    Trichopoulos, Dimitrios
    Neonatal leptin levels are strongly associated with female gender, birth length, IGF-I levels and formula feeding.2005In: Clinical Endocrinology, ISSN 0300-0664, E-ISSN 1365-2265, Vol. 62, no 3, p. 366-71Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: To investigate predictors of circulating leptin in healthy full-term newborns and to explore the relationship with anthropometric variables, serum levels of adiponectin and the major components of the IGF system at birth. To explore whether leptin levels are regulated by breastfeeding vs. formula feeding.

    DESIGN: Observational cross-sectional study.

    PATIENTS: Three hundred and nineteen healthy full-term newborns delivered during 1999 in Athens, Greece.

    MEASUREMENTS: Anthropometric measurements, formula feeding information and blood samples were obtained. Leptin and adiponectin determinations were performed using a radioimmunoassay (RIA).

    RESULTS: Multivariate regression analyses showed that leptin levels were positively associated with female gender, newborn length, ponderal index and IGF-I levels, but not with adiponectin levels. Newborns who were fed exclusively with milk formulas had more than twice the leptin levels of those who were exclusively breastfed.

    CONCLUSIONS: Leptin levels are positively related to female gender and anthropometric characteristics of neonates but, contrary to studies in adults, are not correlated with adiponectin levels. We also found evidence that formula feeding imparts a considerable increase in leptin levels in newborns.

  • 37.
    Reinehr, Thomas
    et al.
    Department of Pediatric Endocrinology, Diabetes and Nutrition Medicine, Vestische Children’s Hospital, University of Witten/ Herdecke, Datteln, Germany.
    Lindberg, Anders
    Pfizer Endocrine Care, Pfizer Health AB, Sollentuna.
    Koltowska-Häggström, Maria
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Ranke, Michael
    University Children’s Hospital, Tubingen, Germany.
    Is growth hormone treatment in children associated with weight gain?: Longitudinal analysis of KIGS data2014In: Clinical Endocrinology, ISSN 0300-0664, E-ISSN 1365-2265, Vol. 81, no 5, p. 721-726Article in journal (Refereed)
    Abstract [en]

    ObjectiveGrowth hormone (GH) increases lean body mass and reduces fat mass. However, the long-term changes in weight status during growth hormone treatment, according to age and weight status at onset of treatment, have not previously been reported in large data sets. MethodsChanges in BMI-SDS between starting GH treatment and attaining near adult height (NAH) were analysed in 2643 children with idiopathic GH deficiency (IGHD), 281 children small for gestational age (SGA), 1661 girls with Turner syndrome (TS), and 142 children with Prader-Willi syndrome (PWS) in the KIGS database. ResultsBMI-SDS increased significantly between onset of GH treatment and NAH (IGHD:+029, SGA:+069, TS:+048) except in PWS (-002). These increases were greater in children with younger age at onset of GH treatment (significant in all indications) and with lower doses of GH treatment (significant in IGHD & TS) in multiple linear regression analyses also including gender, duration of GH treatment, BMI-SDS and height-SDS at onset of treatment, and birth weight-SDS. Obese children at onset of GH treatment decreased their BMI-SDS, while underweight and normal weight children at onset of GH treatment increased their BMI-SDS independently of GH treatment indication. ConclusionsLong-term GH treatment was associated with changes in weight status, which were beneficial for underweight and obese children independent of the indication for GH. However, the increase in BMI-SDS in normal weight children treated with GH needs to be investigated in future prospective longitudinal studies to analyse whether this represents an increase of fat mass, lean body mass or both.

  • 38. Ross, Ian
    et al.
    Boulle, Andrew
    Soule, Steven
    Levitt, Naomi
    Pirie, Fraser
    Karlsson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Mienie, Japie
    Yang, Ping
    Wang, Hongjie
    She, Jin-Xiong
    Winter, William
    Schatz, Desmond
    Autoimmunity predominates in a large South African cohort with addison's disease of mainly European descent despite long-standing disease and is associated with HLA DQB*02012010In: Clinical Endocrinology, ISSN 0300-0664, E-ISSN 1365-2265, Vol. 73, no 3, p. 291-298Article in journal (Refereed)
    Abstract [en]

    P>Objective We sought to determine whether autoimmunity is the predominant cause of Addison's disease in South Africa and whether human leucocyte antigen (HLA) DQ association exists. Design We compiled a national registry of patients from primary care, referral centres and private practices. Patients A total of 144 patients, 94 of European descent, 34 Mixed Ancestry, 5 Asian and 11 Black Africans (mean age 45 center dot 9 years, range 2 center dot 7-88 years; mean duration of disease 13 center dot 1 years, range 0-50 years) and controls were matched for gender and ethnicity. All potential causes were investigated. Results Fifty one per cent of cases (74 patients) were autoimmune in aetiology. Either 21-hydroxylase autoantibodies (72 patients, 50% of entire patient group) or adrenocortical autoantibodies (35 patients, 24%) were present, while 23% of patients had both. None of the Asian (n = 5) or Black (n = 11) patients had evidence of autoimmune disease. Overall 8% of patients had tuberculosis, 4% adrenoleucodystrophy, 1% adrenocorticotrophic hormone resistance syndrome and 6% X-linked adrenal hypoplasia. In those with autoimmune disease primary hypothyroidism (47%), premature ovarian failure (8%) and type 1 diabetes (7%) were the most prevalent accompanying autoimmune conditions. HLA DQB1*0201 alleles predominated in the autoimmune group (DQB1*0201: 65%vs 43% of controls P = 0 center dot 017) with the *0201/*0302 heterozygous genotype being the most prevalent (28%vs 8%P = 0 center dot 02). Conclusions While autoimmunity accounts for at least half of patients with Addison's disease in South Africa and is associated with HLA DQB1*0201, none of the Black Africans or Asians in this cohort had adrenal autoantibodies. Moreover, 21-hydroxylase autoantibodies were detectable in a higher proportion than adrenocortical autoantibodies, especially in those patients with a long history after disease onset.

  • 39.
    Sahoo, Saroj K.
    et al.
    Sanjay Gandhi Postgrad Inst Med Sci, Dept Endocrinol, Lucknow 226014, Uttar Pradesh, India..
    Zaidi, Ghazala
    Sanjay Gandhi Postgrad Inst Med Sci, Dept Endocrinol, Lucknow 226014, Uttar Pradesh, India..
    Srivastava, Rajni
    Sanjay Gandhi Postgrad Inst Med Sci, Dept Clin Immunol, Lucknow, Uttar Pradesh, India..
    Sarangi, Aditya N.
    Sanjay Gandhi Postgrad Inst Med Sci, Dept Gastroenterol, Lucknow, Uttar Pradesh, India..
    Bharti, Niharika
    Sanjay Gandhi Postgrad Inst Med Sci, Dept Endocrinol, Lucknow 226014, Uttar Pradesh, India..
    Eriksson, Daniel
    Karolinska Univ Hosp, Karolinska Inst, Dept Med Solna, Stockholm, Sweden..
    Bensing, Sophie
    Karolinska Univ Hosp, Karolinska Inst, Dept Med Solna, Stockholm, Sweden..
    Kämpe, Olle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Autoimmunity. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Aggarwal, Amita
    Sanjay Gandhi Postgrad Inst Med Sci, Dept Clin Immunol, Lucknow, Uttar Pradesh, India..
    Aggarwal, Rakesh
    Sanjay Gandhi Postgrad Inst Med Sci, Dept Gastroenterol, Lucknow, Uttar Pradesh, India..
    Bhatia, Eesh
    Sanjay Gandhi Postgrad Inst Med Sci, Dept Endocrinol, Lucknow 226014, Uttar Pradesh, India..
    Identification of autoimmune polyendocrine syndrome type 1 in patients with isolated hypoparathyroidism2016In: Clinical Endocrinology, ISSN 0300-0664, E-ISSN 1365-2265, Vol. 85, no 4, p. 544-550Article in journal (Refereed)
    Abstract [en]

    Objective The prevalence of autoimmune polyendocrine syndrome type 1 (APS1) among isolated hypoparathyroidism (HP) or primary adrenal insufficiency (PAI) is not well established. We studied the frequency of APS1 in patients with HP or PAI by measuring interferon-alpha (IFN-alpha) antibody levels, a highly sensitive and specific marker for APS1. Design, patients and measurements In a single-centre cross-sectional study, 37 Indian patients with isolated HP and 40 patients with PAI were tested for IFN-alpha antibody using an indirect ELISA. In patients with elevated IFN-alpha antibody, the autoimmune regulator (AIRE) gene was bidirectionally sequenced. Results Three (8.1%) patients with isolated HP had elevated IFN-alpha antibody levels (range: 367-17382 units; positive titre >56 units). Homozygous or compound heterozygous AIRE mutations were detected in all three patients, including a novel mutation (p.T68P). All three APS1 patients had atypical features. The first patient, diagnosed at 7 years of age, died suddenly 5 months later. The second patient had late-onset HP (at the age of 34 years) and a solitary episode of transient mucocutaneous candidiasis 5 years later. The final patient developed HP at the age of 14 years and premature ovarian insufficiency 14 years later. Interleukin-22 antibodies, as well as most other organ-specific antibodies, were absent in the 3 APS1 patients. All patients with PAI were negative for IFN-alpha antibody. Conclusion Eight percentage of patients with isolated HP had elevated IFN-alpha antibody levels and AIRE mutation-positive APS1. All APS1 patients had atypical clinical features. Testing for IFN-alpha antibody should be considered in patients with idiopathic HP.

  • 40.
    Segersten, Ulrika
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Björklund, Peyman
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Hellman, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Åkerström, Göran
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Westin, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Potentiating effects of non-active/active vitamin D analogues and ketoconazole in parathyroid cells2007In: Clinical Endocrinology, ISSN 0300-0664, E-ISSN 1365-2265, Vol. 66, no 3, p. 399-404Article in journal (Refereed)
    Abstract [en]

    Background and objective: 1,25-dihydroxyvitamin D3 [1α,25(OH)2D3, calcitriol], and its less calcaemic synthetic analogues have therapeutic potential in several diseases, including hyperparathyroidism (HPT). We have suggested that non-1α-hydroxylated (nonactive) vitamin D analogues may present an alternative in tumour cells expressing 25-hydroxyvitamin D3 1α-hydroxylase (1α-hydroxylase). The aim of this study was to investigate biological effects of a non-1α-hydroxylated vitamin D analogue in normal and tumour parathyroid cells. Patients and methods: Effects of vitamin D analogues and ketoconazole on parathyroid hormone (PTH) secretion (radioimmunoassay) and PTH mRNA expression (reverse transcription-polymerase chain reaction) were studied in primary bovine parathyroid cells. Proliferation of tumour cells isolated from HPT patients was determined by thymidine incorporation Results: EB1285, non-1α-hydroxylated precursor of the vitamin D analogue EB1089, suppressed PTH secretion and PTH mRNA level as well as increased expression of 25-hydroxyvitamin D3-24-hydroxylase (24-hydroxylase) in bovine parathyroid cells. EB1285 also inhibited cell proliferation of parathyroid tumour cells from primary (pHPT) and secondary HPT (sHPT) patients. Combined treatment with the cytochrome P450-dependent enzyme inhibitor ketoconazole and EB1285 or with active vitamin D compounds potentiated the suppressive effect on PTH secretion from bovine parathyroid cells. Ketaconazole alone displayed PTH suppression and increased 24-hydroxylase expression. Conclusion: The results support the idea that a non-1α-hydroxylated vitamin D analogue may elicit vitamin D receptor (VDR) effects in 1α-hydroxylase expressing parathyroid tumour cells. Further studies are warranted to elucidate whether precursor vitamin D analogues as well as inhibitors of 24-hydroxylase present therapeutic alternatives in patients suffering from HPT.

  • 41.
    Seneviratne, Sumudu N.
    et al.
    Univ Auckland, Liggins Inst, Auckland, New Zealand.;Univ Colombo, Fac Med, Dept Paediat, Colombo, Sri Lanka..
    Derraik, Jose G. B.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health. Univ Auckland, Liggins Inst, Auckland, New Zealand.;Univ Auckland, A Better Start Natl Sci Challenge, Auckland, New Zealand..
    Jiang, Yannan
    Univ Auckland, Dept Stat, Auckland, New Zealand..
    McCowan, Lesley M. E.
    Univ Auckland, Dept Obstet & Gynaecol, Auckland, New Zealand..
    Gusso, Silmara
    Univ Auckland, Liggins Inst, Auckland, New Zealand..
    Biggs, Janene B.
    Univ Auckland, Liggins Inst, Auckland, New Zealand..
    Parry, Graham K.
    Univ Auckland, Dept Stat, Auckland, New Zealand..
    Chiavaroli, Valentina
    Univ Auckland, Liggins Inst, Auckland, New Zealand..
    Cutfield, Wayne S.
    Univ Auckland, Liggins Inst, Auckland, New Zealand.;Univ Auckland, A Better Start Natl Sci Challenge, Auckland, New Zealand..
    Hofman, Paul L.
    Univ Auckland, Liggins Inst, Auckland, New Zealand..
    Nulliparity is associated with subtle adverse metabolic outcomes in overweight/obese mothers and their offspring2017In: Clinical Endocrinology, ISSN 0300-0664, E-ISSN 1365-2265, Vol. 87, no 5, p. 545-551Article in journal (Refereed)
    Abstract [en]

    Background: We aimed to evaluate metabolic outcomes in overweight/obese nulliparous and multiparous women and their offspring.

    Study design: Seventy-two overweight and obese women who participated in a randomized controlled trial of exercise in pregnancy were included in the study, comparing 18 nulliparous and 54 multiparous women and their singleton offspring. Women were assessed at 19 and 36 weeks of gestation. Fetal growth was measured using standard obstetric ultrasound techniques. Cord blood was collected at birth. Maternal and offspring body composition was assessed using DXA similar to 2 weeks after delivery.

    Results: Nulliparous women had higher HbA1c in the third trimester of pregnancy than multiparous women (5.48% vs 5.29%; P=.002) and were more insulin-resistant based on the surrogate marker sex hormone-binding globulin (354 vs 408 nmol/L; P=.047). Nulliparous women also had higher levels of the inflammatory marker tumour necrosis factor-alpha (4.74 vs 3.62 pg/mL; P=.025). At birth, the offspring of nulliparous women were on average 340 g (P=.013) and 0.69 standard deviation scores (P=.026) lighter than those born of multiparous women. Cord blood data showed lower insulin-like growth factor-II (P=.026) and higher IGF binding protein-1 (P=.002) levels in the offspring of nulliparous women. In addition, a less favourable metabolic profile was observed in the offspring of nulliparous women, as indicated by higher triglyceride (P<.001) and interleukin-6 (P=.039) concentrations.

    Conclusions: Infants born of nulliparous overweight and obese women appear to be exposed to a less favourable metabolic environment in utero, with evidence of subtle adverse metabolic outcomes at birth compared to infants of overweight/obese multiparous women.

  • 42. Siyambalapitiya, S
    et al.
    Jonsson, P
    Koltowska-Häggstrom, M
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Gaillard, R
    Ho, K
    Ross, M
    Cross-sectional analysis of testosterone therapies in hypopituitary men on stable pituitary hormone replacement2009In: Clinical Endocrinology, ISSN 0300-0664, E-ISSN 1365-2265, Vol. 70, no 6, p. 907-913Article in journal (Refereed)
    Abstract [en]

    The last decade has seen a proliferation in options for testosterone replacement. However, little is known as to the benefits of different treatment modalities. Our objective was to determine the testosterone prescription pattern and to examine the impact on various outcome measures. A total of 816 adult-onset hypopituitary males on stable pituitary replacement for at least 1 year were identified from the KIMS database. Patients were classified as either eugonadal (n = 106), or hypogonadal (n = 710) on intramuscular (IM, n = 558), oral (n = 74), transdermal (n = 61), and depot (n = 17) testosterone. After 1 year of stable pituitary replacement therapy, body composition, cardiovascular parameters, GH replacement and quality of life were not significantly different in androgen-replaced hypogonadal patients compared to eugonadal patients. There were no differences in outcome variables within the hypogonadal group according to the testosterone replacement regimen used and no difference in response to GH therapy. The majority of hypopituitary patients in the last decade have received IM testosterone. Body composition, cardiovascular parameters, GH replacement and quality of life were not different between eugonadal and hypogonadal patients and were not differentially affected by the mode of testosterone replacement. These findings are reassuring that there is no major difference in response to different testosterone replacement regimens.

  • 43. Tjörnstrand, Axel
    et al.
    Casar Borota, Olivera
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology.
    Heurling, Kerstin
    Schöll, Michael
    Gjertsson, Peter
    Himmelman, Jakob
    Itsenko, Oleksiy
    Ragnarsson, Oskar
    Filipsson Nyström, Helena
    Lower 68 Ga-DOTATOC Uptake in Non-Functioning Pituitary Neuroendocrine Tumors Compared to Normal Pituitary Gland - a Proof-of-Concept Study.2019In: Clinical Endocrinology, ISSN 0300-0664, E-ISSN 1365-2265Article in journal (Refereed)
    Abstract [en]

    OBJECTIVES: 68 Ga-DOTATOC PET targets somatostatin receptors (SSTRs) and is well established for the detection of SSTR-expressing tumors, such as gastrointestinal neuroendocrine tumors. Pituitary adenomas, recently designated as pituitary neuroendocrine tumors (PitNETs), also express SSTRs, but there has been no previous evaluations of 68 Ga-DOTATOC PET in PitNET patients. The aim of this pilot study was to evaluate the diagnostic properties of 68 Ga-DOTATOC PET in the most common PitNET, i.e. non-functioning (NF)-PitNET.

    DESIGN/METHODS: NF-PitNET patients (n = 9) and controls (n = 13) were examined preoperatively with 68 Ga-DOTATOC PET for 45 min after tracer injection in dynamic list mode. Tumor specimens were collected during surgery in patients. MRI and PET images were co-registered using PMOD software. The maximum standard uptake value (SUVmax ) was analyzed in manually outlined regions of interest (ROC) around the tumor in patients and around the pituitary gland in controls. Immunohistochemical analyses were conducted on tumor specimens for assessment of tumor cell type and SSTR expression.

    RESULTS: Median SUVmax (IQR) was lower in patients than in controls (3.9 [3.4-8.5] vs 14.1 [12.5-15.9]; P < .01]. In ROC analysis, the area under the curve was 0.87 (P < .01) for SUVmax , with 78% sensitivity and 92% specificity. Immunohistochemical analysis showed NF-PitNETs were of gonadotroph (n = 7) and corticotroph (n = 2) origin. SSTR expression was high for SSTR3, low-to-moderate for SSTR2, and low for SSTR1 and SSTR5.

    CONCLUSIONS: This proof-of-concept study shows that 68 Ga-DOTATOC PET can be used to differentiate between normal pituitary tissue and NF-PitNET.

  • 44.
    Wikiera, Beata
    et al.
    Department of Endocrinology and Diabetology for Children and Adolescents, University of Medicine, Wroclaw, Poland.
    Mulak, Malgorzata
    Department of Ophthalmology, University of Medicine, Wroclaw, Poland.
    Koltowska-Häggström, Maria
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Noczynska, Anna
    Department of Endocrinology and Diabetology for Children and Adolescents, University of Medicine, Wroclaw, Poland.
    The presence of eye defects in patients with Turner syndrome is irrespective of their karyotype2015In: Clinical Endocrinology, ISSN 0300-0664, E-ISSN 1365-2265, Vol. 83, no 6, p. 842-848Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: Published data on eye disorders in patients with Turner syndrome (TS) are limited. We aimed to evaluate the prevalence of eye disorders in patients with TS and assess the association with patient karyotype.

    DESIGN: Cross-sectional, observational study.

    PATIENTS: Eighty-two patients with TS.

    MEASUREMENTS: We evaluated visual acuity (distance and proximity), intraocular pressure, optic system refraction, orthoposition, frontal eye segment, the eye fundus and colour vision. For eye fundus abnormalities, we conducted ultrasound examinations, visual field evaluations and fluorescein angiography. We statistically tested the association between the prevalence of eye disorders and karyotype.

    RESULTS: 50 (61%) patients had monosomy X; 9 (11%) had mosaicism with a normal 46,XX line; 21 (26%) had structural aberrations; and 2 patients (2%) had other chromosomal abnormalities. Eye disorders were diagnosed in 43 (52%) patients, with 29 (35%) patients having multiple eye defects. Defects related to impaired vision were the most common (44%), followed by strabismus (21%), changes in the posterior eye segment (6%), red-green colour deficiency (5%), changes in the anterior eye segment (5%) and nystagmus (4%). Amblyopia was diagnosed in 13 patients (16%). The most common combinations of ophthalmological defects were hypermetropia and astigmatism with or without other eye problems (12 patients). We found no association between the presence of eye defects and karyotype.

    CONCLUSIONS: Detection of eye abnormalities is necessary in all patients directly after being diagnosed with TS to prevent irreversible deterioration of eye function and permanent poor vision. All girls with TS, irrespective of their karyotype, should be referred to an ophthalmologist.

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